The proposal is for continuation of work on the organization of the mammalian spinothalamic tract (STT) and its descending control. The emphasis will be on plastic changes in responsiveness of these neurons following tissue or nerve injury. Such changes may be causally related to the primary and secondary hyperalgesia and allodynia that follows such injuries in humans. Recordings will be made from STT cells in anesthetized monkeys before and after intradermal injection of capsaicin or induction of acute arthritis and in anesthetized rats after peripheral neuropathy or dorsal rhizotomies. It is hypothesized that central sensitization of STT cells will develop in these animal models. This central sensitization will be counteracted by administration of agents that either interfere with the development of sensitization, such as excitatory amino acid (EAA) and substance P (SP) antagonists, or by specific agonists of neurotransmitters that may be released by activation of descending inhibitory pathways. Iontophoretic co-application of EAAs and SP (or possibly other peptides) is suggested to cause central sensitization by activation of second messenger systems. The latter idea will be tested by administration of trans-ACPD, a metabotropic glutamate receptor agonist. The goal is to improve our understanding of the mechanisms of hyperalgesia so that improved drug therapies can be developed.